Esters of optionally 17-alkylated androsta-4,6-diene 3beta, 17beta-diols and intermediates thereto



United States Patent The present invention is concerned with steroidaldienediol esters and especially with novel esters of androsta-4,6-diene-3,l7-diol and l7-alkylandrosta-4,6-diene-3,17- diols, whichcan be represented by the structural formula wherein R and R areselected from the group consisting of hydrogen, lower alkanoyl, and2-carboxypropionyl radicals in such manner that at least one esterfunction is always present; and X is selected from the group consistingof hydrogen and lower alkyl radicals. An additional feature of thisinvention comprises novel intermediates in the manufacture of theinstant esters.

The lower alkanoyl radicals which R and R can represent are, typically,'formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and also thebranched-chain isomers thereof, said groups being the acyl radicals ofalkanoic acids containing fewer than 7 carbon atoms.

Examples of the lower alkyl radicals encompassed by the X term aremethyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched-chainisomers.

Suitable starting materials for the manufacture of the instant17a-alkyl-3fi,17fi-diol esters are the corresponding diols representedby the structural formula diene-3fi,l7,B-di0l. These novel intermediatesare useful also as androgenic agents, which are further characterized bylack of potent anabolicside effects. Acylation of these diols, forexample with a lower alkanoic acid anhydride or with succinic anhydridein pyridine at room temperature, affords the corresponding 3-monoesters.Under similar conditions but at elevated temperatures, the 3,17-diestersresult. Specific examples are the manufacture of3,8-acetoxy-17a-methylandrosta-4,6-dien-l7fi-0l andUta-methylandrosta-4,6-diene-3fi,17B-diol 3,17-diacetate by reactionwith acetic anhydride and pyridine at room temperature and at aboutrespectively.

The instant esters of androsta-4,6-diene-3fl,17B-diol can bemanufactured from the corresponding 17-esters of 178-hydroxyandrosta-4,6-dien-3-one. Reduction of these keto compounds, forexample by the process described supra, affords the instant 17,8-(loweralkanoyl)oxyandrosta-4,6-dien-3[3-ols. A specific illustration of thismethod is the reaction of 17fl-acet0xyandrosta-4,6-die11-3- ne intetrahydrofuran with lithium tertiary-butoxy aluminum hydride to yield17;?-acetoxyandrosta-4,6-dien-35-01. The latter 17,8-(loweralkanoyl)oxyandrosta-4,6 dien 35-o1s upon treatment with a loweralkanoic acid anhydride in pyridine afford the corresponding3,8,l7/3-diesters. The aforementioned17,8-acetoxyandrosta-4,6-dien-3,8-ol, for example, yieldsandroSta-4,6-diene-3/3-l7-diol 3,17-diacetate upon treatment with aceticanhydride and pyridine.

The esters of this invention are useful as result of their Valuablepharmacological properties. They are, for example, androgenic agentswhich lack the potent anabolic side-eifect typical of related prior artcompositions.

This invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples temperaturesare given in degrees centigrade (3.). Quantities of materials areexpressed in parts by weight unless otherwise noted.

Example 1 To a solution of 2 parts of 17B-hydroxy-l7ct-methy1-androsta-4,6-dien-3-one in 66.6 parts of tetrahydrofuran is added 4parts of lithium tertiary-butoxy aluminum hydride, and the reactionmixture is stirred at room temperaturefor about one hour. Tothis'mixture is added carefully moist tetrahydrofuran and chloroform,and the resulting mixture is washed with water, dried over anhydroussodium sulfate, and evaporated to dryness. The residue is trituratedwith ether, and the resulting crystalline product is recrystallized fromacetone to yield pure 17a-methylandrosta-4,6 diene 35,175 diol, M.P.about 235; [oc] =-98 (methanol). It displays infrared maxima at about2.88, 3.38, 6.07, 6.20, 7.05, and 9.78 microns and also ultravioletmaxima at about 232, 239, and 247.5 millimicrons with molecularextinction coefiicients of about 20,400, 23,200, and 15,000,respectively.

Example? To a solution of 5 parts of l7/i-acetoxyandrosta-4,6-

' methylandrosta-4,6-dien-l75-01,

centrated to dryness. The resulting crystalline residue is trituratedwith ether, then recrystallized from acetone-- hexane to afford pure17,B-acetoxyandrosta-4,6-dien-3,B-ol, M.P. about 147-148"; [a] '=-55(chloroform). It displays infrared maxima at about 2.79, 3.38, 5.72,8.92, and 9.40 microns and also ultraviolet maxima at about 232, 239,and 247.5 millimicrons with molecular extinction coefficients of about21,400, 24,000, and 15,700, respectively.

Example 3 A mixture of one part of l7a-methylandrosta-4,6-diene-318,17fl-diol, 2 parts of acetic anhydride, and 10 parts of pyridine isstored at room temperature for about 16 hours, then poured slowly intowater. The resulting crystalline precipitate is separated by filtration,dried, and recrystallized from acetone-hexane to afford pure3,8-acetoxy-17a- M.P. about 139-140". This substance is characterized bymaxima in its infrared absorption spectrum at about 2.90, 3.40, 5.80,6.09, 6.20, 7.26, 8.05, and 10.31 microns.

Example 5 A mixture of one part of 17 a-methylandrosta-4,6-diene-35,17,8-dio1, 2 parts of propionic anhydride, and parts of pyridine isallowed to stand at room temperature for about hours, then poured slowlyinto water. The resulting crude product is separated by filtration,dried, and recrystallized from ether-pentane to afford17a-methyl-3fipropionoxyandroSta-4,6-dien-1718-01, M.P. about 99-100".It displays infrared maxima at about 2.87, 3.40, 5.75, 8.42, 10.40, and11.71 microns.

Example 6 A mixture of 3 parts of 17a-methylandrosta-4,6-diene- 3 {3,178-di0l, 1.5 parts of succinic anhydride, and parts of pyridine is storedat room temperature for about 24v hours, then diluted carefully withWater. The precipitated product is collected by filtration, dried, anddis-- solved in chloroform. The chloroform solution is washedsuccessively with dilute hydrochloric acid and water, dried overanhydrous sodium sulfate, and evaporated to dryness in vacuo to afford aresidue, which is trituratedwith ether to yield a crude crystallineproduct. Recrystallization from acetone affords pure3,8-(2-carboxypropionyl)-1-7amethylandrosta-4,6-dien1718-01, MLP. aboutl65-166; [a] =84.5 (chloroform). This compound is further characterizedby infrared absorption maxima at about 2.84, 3.40, 5.71, 5.80, 8.50,9.210, and 11.55 microns.

Example 7 The substitution of an equivalent quantity of17a-ethylandrosta-4,6-dien-3-one in'the process of Example 1 results inl7ot-ethylandrosta-4,6-diene 3fi,17fl-diol.

Example 8 4 Example 9 When an equivalent quantity ofl7fi-propionoxy-androsta-4,6-dien-3-one is substituted in the process ofExample 2, 17fi-propionoxyandrosta-4,6-dien-3,6-ol is obtained.

Example 10 iAndrosta-4,6-diene3 5,17fi-diol 3,17-dipropionate isproduced by the reaction of 2 parts of17fi-propionoxyandrosta-4,6-dien-3B-ol and 5 parts of propionicanhydride 10 according to the procedure of Example 3.

Example 11 A mixture of one part of l7a-methylandrosta-4,6-diene-3,9,17fi-diol, 2 parts of acetic anhydride, and 5 parts of pyridine isheated at the reflux temperature for about 30 minutes, then cooled anddiluted with ice and Water. Extraction of this aqueous mixture withether affords an organic solution, which is washed successively withdilute dried over anhydrous sodium sulfate, and evaporated to dryness toyield l7u-methylandrosta-4,6-diene-3fl,17l3-diol 3,17-diacetate as anoil. This substance displays infrared maxima at about 3.42, 3.71, and7.90 microns, and ultraviolet maxima at about 231, 238, and 247millimicrons with molecular extinction coefiicients of about 25,000,27,000, and 17,500, respectively.

What is claimed is:

1. A compound of the structural formula wherein R and R are selectedfrom the group consisting of hydrogen, lower alkanoyl, and2-carboxypropionyl radicals, with the provision that at least one estergroup is always present, and X is selected from the group con- 1 sistingof hydrogen and lower alkyl radicals.

2. A compound of the structural formula OH CH:

0 wherein R is a lower alkanoyl radical and X is a lower alkyl radical.

3. A compound of the structural formula wherein R is a loweralkanoylradical.

hydrochloric acid, water, and aqueous sodium bicarbonate, I

4. A compound of the structural formula OR CH:

wherein R is a lower alkanoyl radical.

5. 3fl-acetoxy-17a-methylandrosta 4,6 dien-17p-ol.

dien-175-ol.

8. 17p-acetoxyandrosta-4,6-dien-3 3-o1.

6. 17a-methyl-3 3-propionoxyandrosta 4,6 (lien-17p- 7.3fi-(2-carboxypropionyl) 17a methylandrosta-4,6-

6 9. Androsta-4,6-diene 3 8,175 diol 3,17-cliacetate. 10.17a-methylandrosta 4,6 diene-3,8,17/3-dio1 3,17-

5 wherein R is a lower alkyl radical.

12. 17a-methylandrosta 4,6 diene-3/3,17fi-dio1.

No references cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA